Chemokines are a family of about 50 small proteins that modulate cell trafficking and angiogenesis and also play a significant role in the tumor microenvironment (Vicari et al., 2002, Cytokine Growth Factor Rev, 13:143-154). Depending on their structure, chemokines are classified as C—C chemokines (containing a cysteine-cysteine motif) or C—X—C chemokines (containing a cysteine-X-cysteine motif). Receptors that bind such chemokines thus are classified as members of the CCR family or CXCR family, respectively. One member of the CXCR family is CXCR4, a seven transmembrane G-protein coupled receptor that is predominantly expressed on lymphocytes and that activates chemotaxis. CXCR4 binds the chemokine CXCL12 (SDF-1).
CXCR4 plays a role in embryogenesis, homeostasis and inflammation. Studies with mice engineered to be deficient in CXCR4 or SDF-1 implicate the CXCR4/SDF-1 pathway in organ vascularization, as well as in the immune and hematopoietic systems (Tachibana et al., 1998, Nature, 393:591-594). Moreover, CXCR4 has been shown to function as a coreceptor for T lymphotrophic HIV-1 isolates (Feng et al., 1996, Science, 272:872-877). CXCR4 also has been shown to be expressed on a wide variety of cancer cell types. Additionally, the CXCR4/SDF-1 pathway has been shown to be involved in stimulating the metastatic process in many different neoplasms (Murphy, 2001, N Eng. J Med, 345:833-835). For example, CXCR4 and SDF-1 have been shown to mediate organ-specific metastasis by creating a chemotactic gradient between the primary tumor site and the metastatic site (Muller et al., 2001, Nature, 410:50-56; Murakami et al., 2002, Cancer Res, 62:7328-7334; Hanahan et al., 2003, Cancer Res, 63:3005-3008).
Evidence has been presented suggesting that CXCL12 may be immunosuppressive and may support the stroma surrounding the tumor, shielding it from immune mechanisms that would otherwise result in tumor cell killing (Feig et al., 2013, Proc Natl Acad Sci, 110:20212-20217; Domanska et al., 2013, Eur J Cancer, 49:219-30; Duda et al., 2011, Clin Cancer Res, 17:2074-80; Burger et al., 2006, Blood, 107:1761-7). The refractory nature of many metastatic tumors may result from an immunosuppressive environment surrounding the tumor that prevents activated lymphocytes from accessing the tumor site. It is, therefore, of interest to determine whether disruption of the stromal microenvironment via CXCR4 blockade could increase the tumor's susceptibility to immune-targeted therapies and allow for the penetration of immune cells to the tumor site.